The present invention provides formulations of the intravenous anesthetic drug propofol (2,6-diisopropylphenol) as a phospholipid-coated microdroplet substantially completely devoid of fats or triglycerides. Such formulations offer advantages for chronic use in sedation, where fat (triglyceride) overload is presently an important clinical consideration. The formulation of the present invention is also shown to be bacteriostatic and bactericidal.
Propofol is a hydrophobic, water-insoluble oil. It has been incorporated in a vegetable oil emulsion to overcome the problem of its low water solubility and enable its use as an intravenous anesthetic agent. The clinically-available product (PDR, 1995) is a sterile, nonpyrogenic emulsion containing 1% (w/v) propofol in a white, 10% (w/v) soybean oil in water emulsion stabilized by 1.2% (w/v) lecithin (Diprivan.RTM.). Sterile pharmaceutical compositions of propofol and their use in inducing anesthesia are described in U.S. Pat. Nos. 4,056,635; 4,452,817 and 4,798,846 all to Glen and James. The propofol/soybean oil emulsion has gained widespread use for induction and/or maintenance of anesthesia, for maintenance of monitored anesthesia care and for sedation in the Intensive Care Unit (ICU). It produces rapid onset anesthesia with a short recovery time
Two problems associated with the use of vegetable oil in the commercial 1% propofol/10% soybean oil emulsion are: (1) hyperlipidemia in patients undergoing long-term ICU sedation, and (2) the risk of bacterial contamination secondary to the high lipid content and lack of antimicrobial preservatives.
The present invention provides phospholipid-coated propofol microdroplet formulations (MD-Propofol) which allow propofol to be delivered at a higher "payload" on a weight per volume basis than the current clinically available product without soybean oil, or other fats or triglycerides.
The formulation of propofol for intravenous administration without using soybean oil, fats or triglycerides is an important feature of the present invention. Studies by Gottardis et at., 1989, De Soreruer, et al., 1990, Lindholm, 1992, and Eddieston and Shelly, 1991 have shown that triglyceride overload can become a significant problem when the 1% propofol/10% soybean oil emulsion is used as the sole sedative for long-term ICU sedation. Administration of the propofol/soybean oil emulsion elevates serum lipids in exactly the same way as does the Intralipid.RTM. product on which it is based. It has been reported that if propofol/soybean oil emulsion is given in the ICU for sedation together with IV hyperalimentation, the lipid load may exceed the patient's capacity to clear the IV fats, resulting in "fat overload syndrome". The associated hyperlipidemia can result in increased bilirubin levels, "fatty liver", liver damage and other adverse consequences. It is further noted that lipid tolerance may be reduced in critically ill patients secondary to altered metabolic enzyme systems. Experimentation with a 2% propofol emulsion which delivers less fat per unit propofol has been reported (Ewart et al, 1992; Dewandre et al 1994).
The formulation of propofol for intravenous administration free of the risk of bacterial growth is a second important feature of the present invention. The commercially-available product will grow bacteria and presents a risk of bacterial contamination as the result of its high triglyceride content and lack of antimicrobial preservatives (Arduino et al., 1991; Sosis & Braverman, 1993; PDR, 1995). Phospholipid-coated propofol microdroplets of the present invention do not support the growth of bacteria, and are, in fact, bactericidal.
The phospholipid-coated microdroplets at about 0.1 .mu.m diameter droplet of drug in the oil state, coated with a stabilizing monolayer of phospholipid are described in my earlier patents U.S. Pat. Nos. 4,622,219 and 4,725,442, the disclosures of which are hereby incorporated by reference. Microdroplet formulations have been made for many compounds including methoxyflurane, isoflurane and Vitamin E. The present invention provides a formulation of microdroplet propofol which allows the administration of propofol without the fat.